Antipsychotic Drugs Influence Dopamine Neuron Terminals via Action on D2-receptors and Vesicles
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. Department of Pharmaceutical Sciences Honors Theses; 2013
Dopamine D2 antagonist antipsychotic drugs share the effects of increasing dopamine synthesis, dopamine neuron firing rate, and dopamine and DOPAC levels. These antagonists all raise extracellular dopamine to approximately 163% of control and DOPAC levels to approximately 200% of control without changing tissue level of dopamine. Variability in striatal tissue DOPAC level (190 – 350% of control) and rates of dopamine synthesis (190‐378% of control) reported after administration of various antipsychotic drugs gives evidence that these parameters are influenced by factors besides the antagonism of the D2 receptor. We used a computational model of dopaminergic terminals in the striatum to determine what parameters other than D2 receptors might be targets for the drugs. Simulation model results suggest that D2 receptor antagonism results in a slight increase in rate of dopamine exocytosis accompanied by a small increase in rate of dopamine synthesis needed to maintain the increase in rate of exocytosis and a small increase in rate of dopamine synthesis specifically dedicated to DOPAC secretion. Simulation model results also suggest that variable increases in levels of tissue DOPAC result from increases in passive diffusion of dopamine out from vesicles coupled with an increase in rate of dopamine synthesis required to maintain tissue levels of dopamine. Biochemical data reported in the literature suggests changes in passive diffusion depend on the ability of the antipsychotic drug to diffuse into and alkalinize vesicles. This variable increase in tissue DOPAC, but invariable increase in extracellular dopamine across all antipsychotic drugs, provides evidence that DOPAC levels are not a precise indicator of dopamine turnover. These findings also suggest there is a sensor that monitors dopamine vesicular levels and provides feedback to tyrosine hydroxlase activity.
Undergraduate Denman Research Forum - 2nd Place
Academic Major: Pharmaceutical Sciences
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